Erectile dysfunction, or impotence, is a common disorder that occurs in more than 10 million men in the U.S.A. Although psychogenic etiology was thought to be the primary cause of erectile dysfunction, it now is believed that underlying organic diseases are responsible for most instances of erectile dysfunction. This conceptual change is supported by the particularly high incidence of impotence in men with essential hypertension, coronary artery disease and diabetes. In addition, a major mechanism responsible for impotence is an increase in the tone and/or contractility of smooth muscle within the corpus cavemosum penis and penile arteries that impede the modulation of penile blood flow by physiologic regulators. A similar mechanism, an increased tone and/or contractility of vascular smooth muscle, impedes the modulation of blood flow in the coronary, renal, and other arteries of hypertensive, diabetic etc. patients.
Other potential organic causes of erectile dysfunction include endocrine disorders, e.g., testicular failure and hyperprolactinemia; side effects of drugs, e.g., antiandrogens, antihypertensives, anticholinergics, antidepressants, antipsychotics, central nervous system depressants and drugs of habituation or addiction; penile diseases, e.g., Peyronie's disease, previous priapism, and penile trauma; neurological diseases, e.g., anterior temporal lobe lesions, diseases of the spinal cord, loss of sensory input, diseases of nervi erigentes, and diabetic autonomic neuropathy; and vascular diseases, e.g., essential hypertension, aortic occlusion, atherosclerotic occlusion or stenosis of the pudendal artery, venous leak, and diseases of the sinusoid spaces.
Disorders such as essential hypertension, coronary artery disease and diabetes involve an increase in vascular smooth muscle tone which imposes limitations on the modulation of regional blood flow in the kidney, heart, brain and other segments of the vascular bed. Clinical and experimental observations suggest that an imbalance between locally produced Angiotensin II and nitric oxide (NO) leads to an inappropriate tone of vascular smooth muscle resulting in increased blood pressure and altered regional blood flow. Indeed, administrations of nitric oxide synthase (NOS) inhibitors or angiotensin II increase the tone and/or contractility of vascular smooth muscle and systemic blood pressure, thereby decreasing regional blood flow to organs such as the kidney and heart. Conversely, NO, angiotensin II antagonists, renin inhibitors, and angiotensin converting enzyme (ACE) inhibitors decrease the smooth muscle tone and increase regional blood flow to these organs, and decrease systemic blood pressure.
As a modified vascular tissue, ccp produces and secretes the same range of autocrine and paracrine regulators as conventional vascular tissue. The smooth muscle tone of the ccp, however, does not appear to be regulated in the same manner as in the vascular wall. Presently it is postulated that the tone or contractility of ccp is modulated by adrenergic regulation and locally produced NO and endothelin. In the ccp, most studies have been directed to observing the relaxing effects of NO, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and parasympathetic innervation, which also have similar effects on conventional and ccp vascular smooth muscle.
Although both vascular and ccp smooth muscle are contracted by angiotensin II, this peptide is not considered an important regulator of penile blood flow. In fact, it generally is believed that antihypertensive agents, such as ACE inhibitors and angiotensin II antagonists, can cause sexual dysfunction in male patients. Several studies have been conducted to determine whether antihypertensive agents actually cause erectile dysfunction. The results of the studies were inconsistent. Some studies found that ACE inhibitors caused impotence.
Many male patients with hypertensive diabetes and/or coronary artery disease are impotent. One form of treatment for hypertensive patients, .mu. blocker administration, exacerbates impotence. Although this patient population is often treated with renin-angiotensin system inhibitors, several studies have concluded that ACE inhibitors, such as captopril, do not show any effect on improving impotence. (Croog et al, Sexual Symptoms in Hypertensive Patients, Arch Intern Med 148: 788-794, (1988); Suzuki et al, Effects of First-line Antihypertensive Agents on Sexual Function and Sex Hormones, J of Hypertension 6:S649-S651 (1988).
Several therapies have been developed and are currently being used to treat erectile dysfunction. Therapies include treatment with androgens, injection into the corpus cavernosum of smooth muscle relaxing substances such as papaverine, phentolamine, and PGE.sub.1, psychotherapy, penile prostheses, and mechanical devices such as those employing a vacuum to cause erection and a restricting means to prevent venous return at the base of the penis. Injection of smooth muscle relaxing substances into the ccp is an efficient method of treatment, successful in 70-95% of cases. The high rate of success indicate that the increased tone of ccp smooth muscle is the most important cause of erectile dysfunction. However, self injection is inconvenient for a large number of patients, it is frequently painful and may cause detrimental side effects such as priapism and penile fibrosis. Penile prostheses are effective but require surgery.
It would be desirable to have a therapy that could be administered systemically and that could avoid the foregoing drawbacks.